Li X, Li R, Liu G
… +13 more, Qiu D, Mei Y, Xiong Z, Yuan Z, Zhang P, Zhang M, Liu X, Tang H, Zhang Y, Yu X, Liu Y, Sui B, Wang Y
Cephalalgia
· 2026 Jan · PMID 41603449
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BackgroundExcessive iron deposition is associated with migraine occurrence, disease severity, and related dysfunction. The migraine attack is a coordinated, whole-nervous-system event, while previous research has predomi...BackgroundExcessive iron deposition is associated with migraine occurrence, disease severity, and related dysfunction. The migraine attack is a coordinated, whole-nervous-system event, while previous research has predominantly focused on discrete brain regions. This study aims to explore the associations between network-level iron deposition and both disease occurrence and clinical manifestations in migraine using the functional connectome.MethodsSeventy-three migraine patients, including 32 episodic migraine (EM) and 41 chronic migraine (CM), and 37 age- and sex-matched healthy controls (HCs) were recruited. All participants underwent magnetic resonance imaging (MRI) to acquire quantitative susceptibility mapping (QSM) data. First, individual iron deposition maps were defined by comparing iron levels in each patient versus HCs. Next, the network coupling with each patient's site of iron deposition was calculated using seed-based functional connectivity (FC) in a large ( = 1000) normative connectome, termed the iron deposition network map (IDNM). We then performed inter-group analysis to identify disease- and symptom-associated brain regions and measured the FC strength between these regions and the patients' iron deposition maps. Finally, we investigated the relationships between IDNM-derived metrics and various clinical manifestations, including headache characteristics, migraine-related symptoms, disability measures, and comorbidities.ResultsIDNM group comparisons revealed significant differences in the superior temporal gyrus (STG), insula, and cerebellum in both migraine vs. HCs and CM vs. HCs comparisons, whereas no statistically significant differences were found for EM compared to either CM or HCs. FC strength between the peak site of the regions and individual iron deposition maps showed good discriminative performance in receiver operating characteristic (ROC) analysis (AUC > 0.70), effectively distinguishing migraine patients from HCs. Moreover, we identified clinical manifestation-related networks based on the IDNMs: the cerebellum for monthly headache days (MHDs; = 0.349, = 0.003); the orbitofrontal cortex (OFC) and nucleus accumbens (NAC) for poor sleep quality ( = 0.604, < 0.001); and the globus pallidus (GP) for vomiting ( < 0.001).ConclusionNetwork-level iron deposition may distinguish migraine patients from HCs and is associated with clinical manifestations including MHDs, poor sleep quality, and vomiting symptoms, suggesting that iron deposition may play a role in migraine through the functional connectome.
Phillips K, Gokhale K, Damase-Michel C
… +5 more, Dolk H, Nelson-Piercy C, Wakerley BR, Crowe F, Nirantharakumar K
Cephalalgia
· 2026 Jan · PMID 41603448
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ObjectiveTo estimate the risk of miscarriage amongst pregnant women with migraine compared to pregnant women without migraine. To compare the odds of miscarriage in women taking medication for migraine to women with migr...ObjectiveTo estimate the risk of miscarriage amongst pregnant women with migraine compared to pregnant women without migraine. To compare the odds of miscarriage in women taking medication for migraine to women with migraine who did not take medication and to explore this association with different types of medications.DesignMatched cohort study and nested case-control.SettingClinical Practice Research Datalink (CPRD) GOLD pregnancy register. All pregnancies meeting data quality requirements between 2000 and 2019 were eligible for inclusion.ParticipantsCohort study: 193,208 pregnancies of women with migraine were matched one-to-one to women without migraine. Nested case-control: 20,778 pregnancies of women with migraine that ended in miscarriage were matched to 40,122 pregnancies of women with migraine that did not end in miscarriage.Main outcome measuresCohort study: miscarriage recorded in primary care. Nested case-control: odds of miscarriage amongst migraineurs using migraine medication.ResultsMiscarriage occurred in 10% (n = 19,233) of women without migraine compared to 10.8% (n = 20,778) of women with migraine. Having migraine was associated with an 8% higher relative risk of miscarriage (risk ratio (RR) 1.08, 95% confidence interval (CI) 1.06-1.10, p < 0.001) and remained significant after adjustment for demographic factors, body mass index (BMI), smoking and comorbidities (aRR 1.06 95% CI [1.04-1.08][p = 0.001]).Of the pregnancies ending in miscarriage, 719 (3.46%), 380 (1.83%), 173 (0.83%) and 733 (3.52%) were exposed to triptans, amitriptyline, beta-blockers and non-steroidal anti-inflammatory drugs (NSAIDs), respectively. Of the matched pregnancies that did not end in miscarriage, 1099 (2.74%), 542 (1.35%), 294 (0.73%) and 780 (1.94%) were exposed to these medications, respectively.Exposure to triptans, amitriptyline and NSAIDs were associated with a significantly higher odds of miscarriage (aORs 1.24 [1.11-1.38][p < 0.001], 1.25 [1.08-1.45][p = 0.003] and 1.74 [1.57-1.93][p < 0.001] respectively). Beta-blockers were not associated with a higher risk of miscarriage.ConclusionsMigraine and triptan, amitriptyline and NSAID exposure were all associated with higher risk of miscarriage. Further work is needed to understand the potential causative mechanisms.
Brenna E, Ferro M, Sumelahti ML
… +5 more, Cajuso T, Ganna A, Rossi J, Tikkanen E, FinnGen Project
Cephalalgia
· 2026 Jan · PMID 41603368
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AimThis study aimed to identify risk factors associated with non-optimal triptan response among migraine patients, leveraging the unique combination of genetic and longitudinal data available in the FinnGen project.Metho...AimThis study aimed to identify risk factors associated with non-optimal triptan response among migraine patients, leveraging the unique combination of genetic and longitudinal data available in the FinnGen project.MethodsWe analyzed register data from 5351 consistent triptan users within the FinnGen project, focusing on patients who switched triptan medications at least once within a two-year period. We assessed 528 variables, including disease diagnoses, drug purchases and socio-economic status, aiming to evaluate clinical risk factors. Moreover, a genome-wide association study (GWAS) was conducted to explore genetic predispositions to triptan switching behavior in the same cohort of patients. Since no significant single nucleotide polymorphisms (SNPs) were found in the GWAS, a supplementary analysis based on previously reported SNPs associated with migraine susceptibility and triptan response was performed.ResultsOur cohort consisted predominantly of women (87%) with an average age of 38 years at the time of their first triptan purchase. In this population of patients who consistently use triptans, 85% of patients did not switch medications, while 9% switched once, 3% switched twice and 3% switched three or more times. Younger patients were more likely to switch medications. Clinical risk factors for switching included fibromyalgia and the use of gastro-oesophageal reflux medications for those who switched twice, and oral cavity disorders, intestinal disorders and gynecological diagnoses for those who switched three or more times. No significant genetic associations were identified.ConclusionsNon-optimal triptan response in migraine patients is associated with several clinical characteristics, including prior medical diagnoses and the use of other medications. No genetic associations were observed in this cohort.
Do TP, Aagaard SM, Ashina H
… +5 more, Steiner TJ, Micheelsen A, Hammer-Helmich L, Mehta A, Ashina M
Cephalalgia
· 2026 Jan · PMID 41603302
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BackgroundThe HEAD-WINd study was designed to examine the burden, characteristics and lived experiences of headache disorders in the Danish adult population. By integrating data from surveys, a smartphone application, an...BackgroundThe HEAD-WINd study was designed to examine the burden, characteristics and lived experiences of headache disorders in the Danish adult population. By integrating data from surveys, a smartphone application, and national health and social registries, the study addresses limitations of prior epidemiological research.MethodsA random sample of Danish residents aged 18-75 years were invited to participate ("base population"). Two nested cohorts were recruited using a population-based approach: (i) a survey cohort consisting of individuals reporting active headache disorders ("headache population") and (ii) a smartphone application cohort, derived from the headache population, which was followed longitudinally for 12 weeks. Data from these cohorts were enriched with data from national health and social registries, including information on medication use, hospital records, socioeconomic status and healthcare utilization. An adapted version of the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation (HARDSHIP) questionnaire was used to classify multiple headache disorders and assess headache-attributed burden.ResultsOf the 100,030 invited individuals, 28,617 (28.6%) completed the general survey. Among them, 15,571 (54.4%) reported experiencing headache in the preceding year; 14,074 (90.4%) completed the headache-specific survey. In total, 663 individuals (4.7%) participated in the app-based longitudinal study. The mean ± SD participant age was 53.2 ± 15.5 years, 57.4% were women and the mean ± SD body mass index was 26.8 ± 7.4 kg/m².ConclusionsHEAD-WINd has established a comprehensive, population-based cohort of Danish residents, including individuals both with and without headache disorders. This resource provides a framework for generating population-level insights into the burden and management of headache disorders.
Cephalalgia
· 2026 Jan · PMID 41593030
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Observational studies have linked migraine to a wide range of risk factors and diseases, although the causality of these associations is uncertain. Mendelian randomization (MR) is an analytic paradigm that exploits germl...Observational studies have linked migraine to a wide range of risk factors and diseases, although the causality of these associations is uncertain. Mendelian randomization (MR) is an analytic paradigm that exploits germline genetic variants as natural experiments, providing a framework for causal inference from observational data. In this narrative review, we summarize the core principles and assumptions of MR and highlight methodological considerations unique to its application to migraine research. We review key MR findings across several domains of migraine research, noting areas of consistent evidence, as well as conflicting results. We then discuss limitations of MR in the context of migraine research, emphasizing that MR is not a panacea for causal inference. We conclude by underscoring the need for interdisciplinary collaboration between methodologists and domain experts to prioritize patient-relevant questions, refine analytic approaches and translate genetic insights into more effective therapies.